10-5960405-T-G

Variant names:

• chr10-5960405-T-G
• rs2228059
• NM_002189.4:c.545A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002189.4(IL15RA):​c.545A>C​(p.Asn182Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,613,568 control chromosomes in the GnomAD database, including 208,485 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23846 hom., cov: 30)
  • Exomes 𝑓: 0.50 (184639 hom.)
• Consequence: IL15RA NM_002189.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.137
• Publications: 69 publications found

Genes affected

IL15RA (HGNC:5978): (interleukin 15 receptor subunit alpha) This gene encodes a cytokine receptor that specifically binds interleukin 15 (IL15) with high affinity. The receptors of IL15 and IL2 share two subunits, IL2R beta and IL2R gamma. This forms the basis of many overlapping biological activities of IL15 and IL2. The protein encoded by this gene is structurally related to IL2R alpha, an additional IL2-specific alpha subunit necessary for high affinity IL2 binding. Unlike IL2RA, IL15RA is capable of binding IL15 with high affinity independent of other subunits, which suggests distinct roles between IL15 and IL2. This receptor is reported to enhance cell proliferation and expression of apoptosis inhibitor BCL2L1/BCL2-XL and BCL2. Multiple alternatively spliced transcript variants of this gene have been reported.[provided by RefSeq, Apr 2010]

ENSG00000300557 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.351063E-6).
• BP6: Variant 10-5960405-T-G is Benign according to our data. Variant chr10-5960405-T-G is described in ClinVar as Benign. ClinVar VariationId is 1232028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002189.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL15RA	NM_002189.4	MANE Select	c.545A>C	p.Asn182Thr	missense	Exon 4 of 7	NP_002180.1
	IL15RA	NM_001256765.1		c.803A>C	p.Asn268Thr	missense	Exon 5 of 8	NP_001243694.1
	IL15RA	NM_001351095.2		c.620A>C	p.Asn207Thr	missense	Exon 4 of 7	NP_001338024.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL15RA	ENST00000379977.8	TSL:1 MANE Select	c.545A>C	p.Asn182Thr	missense	Exon 4 of 7	ENSP00000369312.3
	IL15RA	ENST00000397248.6	TSL:1	c.803A>C	p.Asn268Thr	missense	Exon 5 of 8	ENSP00000380421.3
	IL15RA	ENST00000622442.4	TSL:1	c.698A>C	p.Asn233Thr	missense	Exon 5 of 8	ENSP00000480949.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83149 AN: 151734 Hom.: 23812 Cov.: 30

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.523

GnomAD2 exomes AF: 0.507 AC: 127468 AN: 251432 AF XY: 0.503

Gnomad AFR exome AF: 0.723

Gnomad AMR exome AF: 0.532

Gnomad ASJ exome AF: 0.522

Gnomad EAS exome AF: 0.422

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.485

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.500 AC: 731339 AN: 1461716 Hom.: 184639 Cov.: 50 AF XY: 0.500 AC XY: 363600 AN XY: 727166

African (AFR) AF: 0.718 AC: 24023 AN: 33480

American (AMR) AF: 0.531 AC: 23748 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 13862 AN: 26134

East Asian (EAS) AF: 0.435 AC: 17283 AN: 39686

South Asian (SAS) AF: 0.536 AC: 46234 AN: 86256

European-Finnish (FIN) AF: 0.456 AC: 24335 AN: 53418

Middle Eastern (MID) AF: 0.517 AC: 2979 AN: 5766

European-Non Finnish (NFE) AF: 0.493 AC: 548182 AN: 1111864

Other (OTH) AF: 0.508 AC: 30693 AN: 60388

GnomAD4 genome AF: 0.548 AC: 83242 AN: 151852 Hom.: 23846 Cov.: 30 AF XY: 0.544 AC XY: 40381 AN XY: 74220

African (AFR) AF: 0.709 AC: 29368 AN: 41410

American (AMR) AF: 0.519 AC: 7915 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1854 AN: 3464

East Asian (EAS) AF: 0.431 AC: 2226 AN: 5160

South Asian (SAS) AF: 0.524 AC: 2505 AN: 4782

European-Finnish (FIN) AF: 0.433 AC: 4574 AN: 10554

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33082 AN: 67904

Other (OTH) AF: 0.523 AC: 1104 AN: 2110

Alfa AF: 0.500 Hom.: 66218

Bravo AF: 0.561

TwinsUK AF: 0.489 AC: 1812

ALSPAC AF: 0.483 AC: 1861

ESP6500AA AF: 0.719 AC: 3167

ESP6500EA AF: 0.489 AC: 4202

ExAC AF: 0.512 AC: 62156

Asia WGS AF: 0.494 AC: 1720 AN: 3478

EpiCase AF: 0.483

EpiControl AF: 0.477

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 18, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21085059)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.39
DANN	Benign	0.41
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.049	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N
PhyloP100		0.14
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.060
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.062
MPC		0.11
ClinPred		0.0091	T
GERP RS		1.1
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.073
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2228059; hg19: chr10-6002368; COSMIC: COSV66092735;